Enantioselective Synthesis of α-Hydroxyamino Ketones by a Chiral Phosphine–Silver Complex Catalyzed N-Nitroso Aldol Reaction

Abstract

A catalytic asymmetric N-nitroso aldol reaction of alkenyl trifluoroacetates with nitrosoarenes was achieved using a DTBM-SEGPHOS·AgOTf complex as the chiral precatalyst and KHMDS as the base precatalyst in the presence of methanol. Optically active α-hydroxyamino ketones with up to 89% ee were regioselectively obtained in moderate to high yields not only from acyclic alkenyl esters but also from cyclic ones through the in situ generated chiral silver enolates.

Key words

asymmetric catalysis - alkenyl ester - nitroso aldol reaction - nitrosoarene - silver

Publication History

Received: 20 September 2022

Accepted after revision: 05 October 2022

Accepted Manuscript online:
05 October 2022

Article published online:
03 November 2022

• References and Notes


For representative examples, see:
• 1a Myers MC, Wang J, Iera JA, Bang J.-K, Hara T, Saito S, Zambetti GP, Appella DH. J. Am. Chem. Soc. 2005; 127: 6152
• 1b Meltzer PC, Butler D, Deschamps JR, Madras BK. J. Med. Chem. 2006; 49: 1420
• 1c Nchinda AT, Chibale K, Redelinghuys P, Sturrock ED. Bioorg. Med. Chem. Lett. 2006; 16: 4612
• 1d Carroll FI, Blough BE, Abraham P, Mills AC, Holleman JA, Wolckenhauer SA, Decker AM, Landavazo A, McElroy KT, Navarro HA, Gatch MB, Forster MJ. J. Med. Chem. 2009; 52: 6768
• 2 Evans RW, Zbieg JR, Zhu S, Li W, MacMillan DW. C. J. Am. Chem. Soc. 2013; 135: 16074
• 3 Várdi A, Palmer TC, Haselton N, Afonin D, Subrath JJ, Rouzic VL, Hunkele A, Pasternak GW, Marrone GF, Borics A, Majumdar S. ACS Chem. Neurosci. 2015; 6: 1570
• 4a Ramakrishna I, Bhajammanavar V, Mallik S, Baidya M. Org. Lett. 2017; 19: 516

For reviews on N-nitroso aldol reactions see:
• 4b Yamamoto H, Momiyama N. Chem. Commun. 2005; 3514
• 4c Merino P, Tejero T, Delso I, Matute R. Synthesis 2016; 48: 653
• 4d Dana S, Ramakrishna I, Baidya M. Synthesis 2017; 49: 3281

For notable examples of N-nitroso aldol reactions promoted by organocatalysts, see:
• 5a Momiyama N, Yamamoto H. J. Am. Chem. Soc. 2005; 127: 1080
• 5b Kano T, Ueda M, Takai J, Maruoka K. J. Am. Chem. Soc. 2006; 128: 6046
• 5c Palomo C, Vera S, Velilla I, Mielgo A, Gómez-Bengoa E. Angew. Chem. Int. Ed. 2007; 46: 8054
• 5d Zhang T, Cheng L, Liu L, Wang D, Chen Y.-J. Tetrahedron: Asymmetry 2010; 21: 2800
• 5e Yang H.-J, Dai L, Yang S.-Q, Chen F.-E. Synlett 2012; 23: 948
• 5f Kano T, Shirozu F, Maruoka K. J. Am. Chem. Soc. 2013; 135: 18036
• 5g Maji B, Yamamoto H. Angew. Chem. Int. Ed. 2014; 53: 8714
• 5h Kano T, Shirozu F, Maruoka K. Org. Lett. 2014; 16: 1530
• 5i Xu C, Zhang L, Luo S. Angew. Chem. Int. Ed. 2014; 53: 4149
• 5j Xu C, Zhang L, Luo S. Org. Lett. 2015; 17: 4392
• 5k Macharia J, Wambua V, Hong Y, Harris L, Hirschi JS, Evans GB, Vetticatt MJ. Angew. Chem. Int. Ed. 2017; 56: 8756
• 5l Chen W, Wang Y, Mi X, Luo S. Org. Lett. 2019; 21: 8178

For examples of N-nitroso aldol reactions catalyzed by chiral Lewis acids (Ag, Sc, Sn, Cu, Mg, and Ra), see:
• 6a Momiyama N, Yamamoto H. J. Am. Chem. Soc. 2004; 126: 5360
• 6b Yamamoto Y, Momiyama N, Yamamoto H. J. Am. Chem. Soc. 2004; 126: 5962
• 6c Shen K, Liu X, Wang G, Lin L, Feng X. Angew. Chem. Int. Ed. 2011; 50: 4684
• 6d Yanagisawa A, Fujinami T, Oyokawa Y, Sugita T, Yoshida K. Org. Lett. 2012; 14: 2434
• 6e Maji B, Baidya M, Yamamoto H. Chem. Sci. 2014; 5: 3941
• 6f Zhang J, Fu K, Lin L, Lu Y, Liu X, Feng X. Chem. Eur. J. 2018; 24: 4289
• 7 Yanagisawa A, Lin Y, Takeishi A, Yoshida K. Eur. J. Org. Chem. 2016; 5355
• 8a Gil J, Medio-Simon M, Mancha G, Asensio G. Eur. J. Org. Chem. 2005; 1561
• 8b Claraz A, Leroy J, Oudeyer S, Levacher V. J. Org. Chem. 2011; 76: 6457
• 9a In our previous study on the chiral silver(I)-catalyzed asymmetric allylation of aldehydes, we showed that a considerable amount of an inert 2:1 complex of BINAP/silver(I) salt was formed accompanied by a reactive 1:1 complex when BINAP was added to an equimolar amount of the silver salt in MeOH. In the reaction, a 0.6:1 mixture of BINAP/silver(I) salt was found to produce the desired 1:1 complex without the formation of the 2:1 complex:
• 9b Yanagisawa A, Kageyama H, Nakatsuka Y, Asakawa K, Matsumoto Y, Yamamoto H. Angew. Chem. Int. Ed. 1999; 38: 3701
• 9c Yanagisawa A, Nakatsuka Y, Asakawa K, Kageyama H, Yamamoto H. Synlett 2001; 69
• 9d Yanagisawa A, Nakatsuka Y, Asakawa K, Wadamoto M, Kageyama H, Yamamoto H. Bull. Chem. Soc. Jpn. 2001; 74: 1477
• 10 Typical Experimental Procedure for the Asymmetric N-Nitroso Aldol Reaction Catalyzed by (R)-DTBM-SEGPHOS·(AgOTf)₂ and KHMDS: Synthesis of 2-[Hydroxy(2-isopropylphenyl)amino]-1-phenylpentan-1-one (3eg, Entry 2 in Table 3 Entry 7 in Table 4, and Entry 4 in Table 5) AgOTf (51.3 mg, 0.20 mmol) was dissolved in dry THF (2 mL) under an argon atmosphere and with direct light excluded at room temperature. To the solution was added a 0.5 mol/L solution of KHMDS in toluene (200 μL, 0.1 mmol) at –40 °C and stirred for 30 min at this temperature. Subsequently, a solution of (R)-DTBM-SEGPHOS (23.6 mg, 0.02 mmol) in dry THF (1 mL) was added and stirred at –40 °C for 30 min. Then a solution of 1-isopropyl-2-nitrosobenzene (2g, 74.6 mg, 0.50 mmol) in dry MeOH (2 mL) and alkenyl trifluoroacetate 1e (230 μL, 1.0 mmol) were successively added to the resulting solution at this temperature. After stirring at –40 °C for 2 h, the mixture was treated with MeOH (3 mL) and stirred at this temperature for 20 min. Then, the mixture was filtered with a glass filter funnel filled with Celite^® and washed with Et₂O, and the combined filtrate and washes were concentrated in vacuo. The residual crude product was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane as the eluant to give corresponding α-hydroxyamino ketone 3eg (146.4 mg, 94% yield). The enantiomeric ratio of the N-adduct was determined to be 89% ee by HPLC analysis using a chiral column (Daicel Chiralpak AS-H, hexane–i-PrOH (80:1), flow rate = 1.0 mL/min) t ₁ = 15.6 min (minor), t ₂ = 32.4 min (major). Spectral Data of the Product ¹H NMR (396 MHz, CDCl₃): δ = 7.98 (d, J = 7.1 Hz, 2 H), 7.58 (m, 1 H), 7.40–7.51 (m, 3 H), 7.27–7.35 (m, 1 H), 7.13–7.19 (m, 2 H), 6.57 (s, 1 H), 4.76 (t, J = 6.7 Hz, 1 H), 3.67 (sept, J = 7.0 Hz, 1 H), 1.76–1.85 (m, 2 H), 1.30–1.43 (m, 2 H), 1.26 (dd, J = 15.2, 7.0 Hz, 6 H), 0.83 (t, J = 7.5 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 202.7, 147.2, 143.9, 136.5, 133.4, 128.6 (2 C), 128.4 (2 C), 126.4, 126.2, 126.1, 121.6, 70.7, 32.1, 26.6, 24.6, 23.5, 19.5, 14.0. IR (neat): 3409, 2961, 2871, 1682, 1597, 1486, 1447, 1383, 1232, 1086, 1032, 1002, 968, 908, 756, 731 cm^–1. MS (ESI): m/z calcd for [C₂₀H₂₅O₂NNa]⁺ [M + Na]⁺: 334.1778; found: 334.1773; [α]_D ^14.2 +16.0 (c 1.0, CHCl₃, 89% ee).
• 11 Bannykh AV, Bakulina OY, Dar’in DV, Krasavin M. Mendeleev Commun. 2019; 29: 337
• 12 Guo W, Luo Y, Sung HH.-Y, Williams ID, Li P, Sun J. J. Am. Chem. Soc. 2020; 142: 14384
• 13 The absolute stereochemistry of cyclic α-hydroxyamino ketones has not yet been determined.

Two examples of the synthesis of achiral silver alkoxides have been reported:
• 14a Edworthy IS, Rodden M, Mungur SA, Davis KM, Blake AJ, Wilson C, Schröder M, Arnold PL. J. Organomet. Chem. 2005; 690: 5710
• 14b Reisinger A, Himmel D, Krossing I. Angew. Chem. Int. Ed. 2006; 45: 6997
• 15 Although it is difficult to refer to the origin of N/O selectivity in the present nitroso aldol reaction at this stage, acyclic alkenyl esters with Z configuration exhibit higher N-selectivity compared to cyclic alkenyl esters.⁷ In addition, chiral phosphines have been found to affect N/O selectivity to some extent.⁷